Over 31 million Americans describe chronic sinusitis as a major health problem. Despite its high prevalence and the fact that millions of dollars are spent on treatment, there have been essentially no definitive studies of the etiology, pathogenesis and therapy of this condition. Epithelial inflammation and hyperplasia are a consistent and striking feature of chronic sinusitis. Epithelial thickening, in fact, represents the abnormality, imaged by CT and MRI scans, that is used to support the diagnosis. We hypothesize that certain individuals have a predisposition to developing sinusitis and that, in these patients, environmental influences, such as viruses, allergens and pollution, can act as precipitating factors. These environmental factors can induce epithelial alterations that trigger inflammation and subsequently decrease mucociliary transport. Stasis of mucus in the sinuses could then facilitate bacterial infections, which may further influence the epithelium. If this cycle is not disrupted, the epithelium develops metaplastic changes and the underlying mucosa proliferates, developing a self-perpetuating cycle that manifests clinically as chronic sinusitis and that is no longer dependent on the bacteria or the anatomy. Thus, we hypothesize that, while alterations in epithelial function may be induced by several different mechanisms, it is the corruption of normal epithelial function that is the final common pathway that leads to the chronic manifestations of the disease. In this program project, we developed a multidisciplinary approach to examine this hypothesis. Surgeons, pediatricians, pulmonologists, infectious disease specialists and allergists have combined with basic scientists. Their efforts focus on the role of the epithelium in patients with the most persistent forms of chronic sinusitis. In particular, we plan to examine four aspects: 1) inherent genetic defects in epithelial function, 2) viral infection as a precipitating factor in altering epithelial cell function, 3) functional alterations in epithelial ion transport and mucus secretion and 4) the interaction of allergic and neurogenic inflammation on nasal and sinus mucosa in vivo. The interactions between investigators should provide novel information about pathogenesis and lead to new management strategies.